Is ABCG5 p.Arg145Cys (c.433C>T) pathogenic?

ABCG5 p.Arg145Cys (c.433C>T) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-28). AlphaMissense: likely benign (0.1639); Ultra-rare (popmax 0.0107%, afr); Associated with sitosterolemia.

What condition is associated with ABCG5 p.Arg145Cys (c.433C>T)?

ABCG5 p.Arg145Cys (c.433C>T) is associated with sitosterolemia (ClinVar).

How common is ABCG5 p.Arg145Cys (c.433C>T) in the general population?

ABCG5 p.Arg145Cys (c.433C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

How is Sitosterolemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCG5 p.Arg145Cys (c.433C>T)?

AlphaMissense predicts likely benign (score 0.1639) — an in-silico prediction, not a clinical call.

ABCG5 p.Arg145Cys

c.433C>T · rs866515397 · VCV1496687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1639 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sitosterolemia

Computational evidence

Protein change
AlphaMissense	0.1639	likely benign
REVEL	0.707	pathogenic-leaning
SaProt	LLR -13.26	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -3.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,646 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.000568% 9/1,585,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,331
East Asian	0.00228%	43,936

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCG5
Protein: p.Arg145Cys
Coding: c.433C>T
MANE Select: NM_022436
dbSNP: rs866515397
Type: single nucleotide variant
Location: chr2:43831837 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 8 PDB
Residue 145: the abc transporter domain; an α-helix

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG5 p.Arg145Gly Uncertain significance ★ ⚠ same residue
ABCG5 p.Arg145His Uncertain significance ★ ⚠ same residue
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.634+1G>C Likely pathogenic ★★ same condition
ABCG5 c.904+1G>A Pathogenic ★★ same condition
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg243Ter Pathogenic ★★ same condition
ABCG5 p.Arg389His Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abcg5-p-arg145cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown